DESCRIPTION (from applicant's abstract): The goal of this proposal is to study the role of the serotonergic system in neural reward pathways. Using classical knockout mice as well as tissue-specific and inducible mice, we propose to investigate the contributions of serotonin receptor subtypes and specific neural circuits to the rewarding and stimulating effects of two families of drugs of abuse: substituted amphetamines (MDMA) and psychostimulants (cocaine). There are numerous suggestions that the serotonergic system contributes to the rewarding effects of cocaine, a potent serotonin (5-HT) and dopamine (DA) uptake blocker. Similarly, some effects of MDMA, a serotonin releaser, have been suggested to be mediated by indirect activation of specific 5-HT receptor subtypes. In the previous funding period, we have shown that mice lacking the 5-HT1B receptor have markedly altered behavioral and biochemical responses to these drugs. Specifically, the stimulatory effects of MDMA on" locomotion are reduced in mice lacking the 5-HTIB receptor. In contrast, the locomotor effects of cocaine are increased in mice lacking the 5-HT1B receptor and these mice are more motivated to self-administer cocaine. We have also shown that compensatory changes have taken place in the knockout mice. In particular, there is an increase in the level of the transcription factor deltafosB, in the nucleus accumbens of the 5- HT1B knockout mice, a phenomenon which is in wild-type mice after chronic cocaine administration. The 5-HT1B knockout mice might therefore represent an animal model of vulnerability to psychostimulants. In the present application, we propose to further characterize these mice in order to determine which neural circuits and which molecular adaptations are responsible for their increased responsiveness to cocaine. We will also characterize two other animal models of serotonergic disfunction. One of them is the DBA/2J inbred strain of mice which we have recently shown to be non responsive to activation of 5-HTIB receptors. The third model is a new knockout line that lacks another serotonin receptor, the 5-HTIA receptor. We have shown that the 5-HTIA knockout mice display an increased locomotor response to cocaine. We propose to first assess whether these mice might also be a model of vulnerability to cocaine and second to determine the neural circuits that underlie their altered response to cocaine. To characterize the neural circuits responsible for the phenotypes of the 5-HTl A and 5-HT I B knockout mice we will use a tissue-specific rescue strategy which consists in reexpressing in the knockout mice the missing receptor in only a subset of the structures where that receptor is normally found.